Cerebral malaria (CM) is an encephalopathy caused by massive sequestration of parasitized erythrocytes in the brain capillaries and associated with elevated plasma levels of TNF, disruption of endothelial intercellular junctions and basal lamina, mononuclear cell margination, ring hemorrhages and Dürck’s granulomas infiltrated with macrophages. During recent years, increased levels of several matrix metalloproteinases (MMPs) have been related to glial activation in either human or murine CM models. Interestingly, in human monocytes phagocytosed hemozoin (HZ, malarial pigment) or HZ-containing trophozoites increase MMP-9 mRNA/protein expression and activity and enhance production of MMP-9-related cytokines TNF and IL-1beta. Present work shows that these HZ/trophozoite phagocytosis effects in human monocytes and their recapitulation by 15(S,R)-hydroxy-6,8,11,13-eicosatetraenoic acid (15-HETE), a potent lipoperoxidation derivative generated by HZ from arachidonic acid via heme-catalysis, were mediated via activation of NF-kappaB transcription pathway. After phagocytosis of HZ/trophozoites or treatment with 15-HETE, the NF-kappaB complex migrated to the nuclear fraction while the inhibitory cytosolic IkappaBalpha protein was phosphorylated and degraded. All HZ/trophozoite/15-HETE effects on MMP-9 activity and TNF/IL-1beta production were abrogated by quercetin, artemisinin and parthenolide, three inhibitors of IkappaBalpha phosphorylation and subsequent degradation, NF-kappaB nuclear translocation, and NF-kappaB-p65 binding to DNA, respectively. In conclusion, enhanced activation of MMP-9, and release of pro-inflammatory cytokines TNF and IL-1beta, a triad of effects dramatically involved in CM pathogenesis, elicited in human monocytes by trophozoite and HZ phagocytosis and recapitulated by 15-HETE, appear to be causally connected to persisting activation of the NF-kappaB system.
Matrix Metalloproteinases and Cerebral Malaria: Hemozoin Enhances MMP-9, TNF and IL-1beta in Human Monocytes through Activation of the NF-kappaB Transcription System
PRATO, Mauro;GALLO, Valentina;GIRIBALDI, Giuliana;KHADJAVI, AMINA;ALDIERI, Elisabetta;ARESE, Paolo
2010-01-01
Abstract
Cerebral malaria (CM) is an encephalopathy caused by massive sequestration of parasitized erythrocytes in the brain capillaries and associated with elevated plasma levels of TNF, disruption of endothelial intercellular junctions and basal lamina, mononuclear cell margination, ring hemorrhages and Dürck’s granulomas infiltrated with macrophages. During recent years, increased levels of several matrix metalloproteinases (MMPs) have been related to glial activation in either human or murine CM models. Interestingly, in human monocytes phagocytosed hemozoin (HZ, malarial pigment) or HZ-containing trophozoites increase MMP-9 mRNA/protein expression and activity and enhance production of MMP-9-related cytokines TNF and IL-1beta. Present work shows that these HZ/trophozoite phagocytosis effects in human monocytes and their recapitulation by 15(S,R)-hydroxy-6,8,11,13-eicosatetraenoic acid (15-HETE), a potent lipoperoxidation derivative generated by HZ from arachidonic acid via heme-catalysis, were mediated via activation of NF-kappaB transcription pathway. After phagocytosis of HZ/trophozoites or treatment with 15-HETE, the NF-kappaB complex migrated to the nuclear fraction while the inhibitory cytosolic IkappaBalpha protein was phosphorylated and degraded. All HZ/trophozoite/15-HETE effects on MMP-9 activity and TNF/IL-1beta production were abrogated by quercetin, artemisinin and parthenolide, three inhibitors of IkappaBalpha phosphorylation and subsequent degradation, NF-kappaB nuclear translocation, and NF-kappaB-p65 binding to DNA, respectively. In conclusion, enhanced activation of MMP-9, and release of pro-inflammatory cytokines TNF and IL-1beta, a triad of effects dramatically involved in CM pathogenesis, elicited in human monocytes by trophozoite and HZ phagocytosis and recapitulated by 15-HETE, appear to be causally connected to persisting activation of the NF-kappaB system.
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